Advanced hormone refractory metastatic prostate cancer (PCa) is the second leading cause of cancer deaths of US men. PCa recurs in approximately 30% of men after their initial treatments of either radical prostatectomy or ionizing radiation therapy. Although Androgen-Deprivation Therapy (ADT) initially causes a regression of the early-stage recurrent PCa, over 80% of the patients under ADT will eventually progress to androgen-independent castration-resistant prostate cancer (CRPCa). Due to the lack of long term benefit of ADT and high frequency of adverse side effects associated with ADT, the identification of a novel agent to prevent PCa progression at an early stage of recurrence is of significant clinical interest.
Cellular Reactive Oxygen Species (ROS) are naturally occurring agents that cause DNA, RNA, lipid and protein damage if their concentrations become too high. ROS levels have been established to be distinctly higher in PCa tissue than in normal prostate. ROS have been shown to propagate prostate cancer development, not only by causing DNA damage, but also by activating an androgen independent survival pathway. Published data have confirmed that androgens induce ROS production in PCa cells via two major factors. First, transcription factor JunD is overexpressed in human PCa cells, when androgen induces oxidative stress, and secondly androgen induces up-regulation of spermidine/spermine acetyl transferase (SSAT), an enzyme responsible for spermidine and spermine catabolism that leads to a rise in cellular ROS levels. In addition, recent data further suggest an intriguing mechanism of PCa progression, where AR-JunD induced SSAT expression causing an increase in ROS levels and consequent upregulation of the transcription factor NF-κB may set up an autocrine feed forward loop of SSAT-ROS-NFκB-SSAT that can sustain ROS production and PCa cell proliferation in the absence of androgen.
Disclosed herein are inhibitors of AR-JunD interaction, which disrupt the AR-JunD complex in PCa cells and thus, block the ROS production, NF-κB activation, and prevent PCa progression. In some embodiments, these inhibitors are effective therapeutic agents for treatment of both androgen-dependent and castrate-resistant prostate cancer.
Androgen activation of AR in LNCaP human PCa cells induces AP-1 transcription factors Fra-2 and JunD. However, only JunD levels and its functional activity remained elevated for 96 h after androgen treatment, when androgen-induced ROS production is observed. JunD may either inhibit or help cellular ROS production, depending on cell type, presence of ROS-generating proteins, growth conditions, etc. Since androgen-induced ROS generation is abrogated by either blocking androgen-induced JunD over-expression with the anti-androgen bicalutamide or silencing JunD protein expression using siRNA, thus JunD activity is deemed necessary for androgen-induced oxidative stress in LNCaP cells.